空卵泡综合征(EFS)是卵巢刺激后无法完全回收卵母细胞。尽管LHCGR和ZP3被鉴定为致病基因,目前还不清楚这些患者的卵母细胞会发生什么,EFS的发病机制仍不清楚。这里,我们发现了6个与EFS和女性不孕症相关的新ZP1突变,这些突变在5个不相关的家庭中被隐性遗传.在CHO-K1细胞中的研究表明,这些突变导致ZP1蛋白的降解或截短。使用卵巢连续切片的免疫组织化学表明,所有的腔前卵泡都具有正常的结构,但是有一个薄的ZP,缺乏ZP1,围绕着正在生长的卵母细胞。正常卵丘-卵母细胞复合体组织中的窦卵泡也有缺陷,导致我们推测缺乏ZP1可能导致卵泡穿刺过程中卵母细胞变性或卵母细胞脆性增加,最终导致EFS。据我们所知,这是第一个提供形态学证据的研究,表明EFS患者正常的窦前卵泡发生和异常的ZP装配.我们的数据为ZP1在人类ZP组装和卵泡发生中的生物学功能提供了更好的理解,并为EFS的发病机理和可能的治疗发展提供了新的见解。
Empty follicle syndrome (EFS) is the complete failure to retrieve oocytes after ovarian stimulation. Although LHCGR and ZP3 were identified as causative genes, it is still unclear what happens to these patients\' oocytes, and the pathogenesis of EFS remains obscure. Here, we identified six novel ZP1 mutations associated with EFS and female infertility that was inherited recessively in five unrelated families. Studies in CHO-K1 cells showed that these mutations resulted in either degradation or truncation of ZP1 protein. Immunohistochemistry using ovarian serial sections demonstrated that all preantral follicles had normal architecture, but with a thin ZP, lacking ZP1, surrounding the growing oocytes. The antral follicles were also defective in normal cumulus-oocyte complex organisation, leading us to speculate that the lack of ZP1 might lead to oocyte degeneration or increased fragility of the oocyte during follicular puncture, ultimately resulting in EFS. To our knowledge, this is the first study that presents morphological evidence showing normal preantral folliculogenesis with abnormal ZP assembly in EFS patients. Our data provides a better understanding of the biological functions of ZP1 in human ZP assembly and folliculogenesis and gives new insights into the pathogenesis of EFS and possible therapeutic developments.